The Impact of Lobular Histology on Breast Cancer Treatment

Breast cancers of lobular histology are not frequently encountered, but are nevertheless the second most common histologic subtype of breast cancer after ductal adenocarcinoma. It is generally accepted that lobular neoplasias arise developmentally from the terminal duct lobular unit (TDLU), where early progenitor cells predetermine either a lobular or ductal histologic fate.[1] Lobular lesions are morphologically distinct, and are characterized by small atypical cells with small nuclei and lack of cohesion between individual cells, as well as loss of e-cadherin expression.[2] The term “lobular intraepithelial neoplasia” (LIN) has been used to describe the spectrum of disease that includes both atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS), since the distinction between the two is often challenging. Although LCIS has historically been considered a “marker” for increased breast cancer risk, emerging molecular evidence supports that LCIS is also likely a precursor of invasive lobular cancer (ILC), albeit with low propensity to progress even in the absence of complete surgical excision.[3,4]

Epidemiologic Factors in the Treatment of LCIS and ILC

LCIS is commonly an incidental finding encountered on biopsy of patients without apparent radiographic or clinical signs at presentation. A Surveillance, Epidemiology, and End Results (SEER)-based study of the age-adjusted incidence rates for LCIS showed a four-fold increase in the incidence of LCIS from 1978 to 1998, which was largely attributable to increased detection in women 50 years or older at diagnosis.[5] Part of the increased incidence was thought to be due to more widespread use of screening mammography, resulting in a greater number of surgical biopsies and incidental histologic diagnoses. However, a concurrent increase in the background reservoir of LCIS in the general population may also exist.

The risk for contralateral breast cancer associated with LCIS has been a matter of ongoing discussion with important clinical implications. Two recent studies using SEER data have reported conflicting findings. One of the studies found an equal number of contralateral and ipsilateral invasive cancers in women with LCIS.[6] The other study also reported on SEER outcome data, and it found that ipsilateral cancers were seen more commonly than contralateral cancers following diagnosis of LCIS.[7] Both studies found a greater-than-expected proportion of ILC among women with a history of LCIS, although the numbers overall were small. Together, these studies support an increased risk of contralateral disease after diagnosis of LCIS; what remains unknown is whether that risk is equivalent to, or exceeds, the magnitude of contralateral risk conferred by any diagnosis of ductal carcinoma in situ or invasive breast cancer. Thus at present, a recommendation for contralateral mastectomy purely on the basis of lobular histology cannot be justified.

Pleomorphic Subtype of Lobular Neoplasia

Both the “classic” and “pleomorphic” subtypes of LCIS have been described, with the pleomorphic variant demonstrating more discohesive cells, greater proliferation rates, and more necrosis than the classic type. Often, classic LCIS and pleomorphic LCIS (PLCIS) are found concurrently. The clinical outcome following treatment for PLCIS has not been systematically studied in a prospective manner, but it is likely to be similar to that of high-grade DCIS, since PLCIS was often misclassified as such prior to increased recognition of this clinical entity. Molecular comparisons between classic LCIS and PLCIS show marked differences, which include a greater degree of genomic instability for both amplifications and deletions, lower ER expression, and higher HER2 expression in PLCIS.[8] This suggests that PLCIS is biologically distinct from classic LCIS, and the morphologically more aggressive appearance of the disease has prompted many to recommend complete surgical excision to negative margins for these patients. This is a reasonable approach until better long-term data confirm whether complete excision of PLCIS has a positive impact on patient outcome.

Surgical Considerations in the Management of Lobular Neoplasias

The case presented here highlights whether the diagnosis of LCIS on core biopsy is always an indication for surgical excision. Data on the prevalence of invasive cancer in this setting have been derived largely from small retrospective single-institution reviews that are likely to have had significant bias in terms of which cases were selected for excision. Thus, the risk of concurrent ILC when core biopsy shows LCIS alone is difficult to estimate, and it ranges widely from 4% to 50% in this setting.[9-12] One study of PLCIS on core biopsy showed that 3 of 10 cases had concurrent invasion; interestingly, all of these were of lobular histology.[13] These findings lead most surgeons to recommend surgical excision for core biopsy–proven LCIS.

An additional surgical issue that continues to be debated is whether LCIS at the margin of an excised specimen increases the risk of locoregional recurrence. Although a few studies have not found increased risk,[14,15] one recent report showed that in 21 patients who underwent re-excision for LCIS or ALH at the margins, 12 patients had additional IBC or DCIS on re-excision, and 7 more had residual LCIS, of which 3 were of the pleomorphic type.[16] Although this study reports on a small series, such findings support thorough review of pathology slides by both surgeon and pathologist to determine the possibility of incomplete excision when lobular intraepithelial neoplasia is present at the margins of excision. Hereditary Predisposition to ILC Linkage analyses in families with both breast and gastric malignancies have identified a hereditary component to ILC attributed to a germline mutation in CDH1, the locus for e-cadherin.[17] E-cadherin is a cell-adhesion protein whose gene is located on chromosome 16q22. Germline mutations at the CDH1 locus have been associated with hereditary diffuse gastric cancer (HDGC) as well as lobular breast cancer conferred through an autosomal dominant pattern of transmission. A deleterious mutation in CDH1 is rare, but when identified it can be associated with up to a 50% lifetime risk of both diffuse gastric cancer and breast cancer.[18] The case illustrates the importance of considering a hereditary predisposition to breast cancer risk in families with a history of both breast cancer and HDGC. This may be of particular value among ethnic groups in which gastric cancers are rare. Detection of a CDH1 mutation may benefit both the patient and her family members, with both prophylactic mastectomy and prophylactic gastrectomy important options to discuss from the viewpoint of cancer risk reduction.

Summary

Lobular neoplasias are a distinct clinical entity with subtle differences in locoregional treatment considerations when compared with ductal cancers. Although overall surgical recommendations do not differ significantly between breast cancers of lobular versus ductal histology, there are important distinctions that should be considered as part of patient care, particularly with respect to recommendations regarding management of the contralateral breast and genetic testing. Because the lobular subtype of breast cancer is underrepresented in studies of molecular prognostic markers, the results of such testing must be interpreted with caution until they are validated specifically in patients with lobular histology. Until then, the mainstay of sound treatment decision-making remains a thorough clinical understanding of the disease and of the factors that can have an impact on outcome.

Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.